Those working in the fields of pharmaceutical formulation and drug delivery continue to be limited by a number of difficulties presented by different active agents. It has proved particularly problematic to provide therapeutically effective formulations for administration of drugs exhibiting low bioavailability and absorption. A well-designed formulation must, at a minimum, be capable of presenting a therapeutically effective amount of the active agent to the desired absorption site, in an absorbable form. Even this minimal functionality can be difficult to achieve, however, e.g., when delivery of a hydrophobic active agent requires interaction with aqueous physiological environments, such as gastric fluids and intestinal fluids.
A number of approaches to formulating active agents having low aqueous solubility are known. One well-known approach uses surfactant micelles to solubilize and transport the therapeutic agent. Micelles are agglomerates of colloidal dimensions formed by amphiphilic compounds under certain conditions. Micelles, and pharmaceutical compositions containing micelles, have been extensively studied and are described in detail in the literature; see, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995). In aqueous solution, micelles can incorporate hydrophobic therapeutic agents in the hydrocarbon core of the micelle, or entangled at various positions within the micelle walls. Although micellar formulations can solubilize a variety of hydrophobic therapeutic agents, the loading capacity of conventional micelle formulations is limited by the solubility of the therapeutic agent in the micelle surfactant. For many therapeutic agents, such solubility is too low to offer formulations that can deliver therapeutically effective doses.
Another conventional approach takes advantage of the increased solubility of hydrophobic therapeutic agents in lipids, particularly oils, i.e., triglycerides. However, traditional lipid-based formulations are generally limited by a low drug loading capacity, which in turn precludes delivery of a therapeutically effective amount of an active agent in a single unit dosage form, a significant drawback in terms of patient compliance. For example, the administration of vitamins typically requires multiple dosage units, as does the administration of a number of pharmacologically active agents (e.g., ritonavir and various other antiviral agents). Furthermore, the properties of oil-based formulations are determined by such factors as the size of the triglyceride/therapeutic agent colloidal particles and the presence or absence of surfactant additives. Although triglyceride-based pharmaceutical compositions are useful in solubilizing and delivering some hydrophobic therapeutic agents, such compositions are subject to a number of significant limitations and disadvantages. Emulsions are thermodynamically unstable, and colloidal emulsion particles will spontaneously agglomerate, eventually leading to complete phase separation. The tendency to agglomerate and phase separate presents problems of storage and handling, and increases the likelihood that pharmaceutical emulsions initially properly prepared will be in a less optimal, less effective, and poorly-characterized state upon ultimate administration to a patient. Uncharacterized degradation is particularly disadvantageous, since increased particle size slows the rate of transport of the colloidal particle and digestion of the oil component, and hence the rate and extent of absorption of the therapeutic agent. These problems lead to poorly-characterized and potentially harmful changes in the effective dosage received by the patient. Moreover, changes in colloidal emulsion particle size are also believed to render absorption more sensitive to and dependent upon conditions in the gastrointestinal tract, such as pH, enzyme activity, bile components, and stomach contents. Such uncertainty in the rate and extent of ultimate absorption of the therapeutic agent severely compromises the medical professional's ability to safely administer therapeutically effective dosages. A further disadvantage of triglyceride-containing compositions is the dependence of therapeutic agent absorption on the rate and extent of lipolysis. Although colloidal emulsion particles can transport hydrophobic therapeutic agents through the aqueous environment of the gastrointestinal tract, ultimately the triglyceride must be digested and the therapeutic agent must be released in order to be absorbed through the intestinal mucosa. The triglyceride carrier is emulsified by bile salts and hydrolyzed, primarily by pancreatic lipase. The rate and extent of lipolysis, however, are dependent upon several factors that are difficult to adequately control.
Hydrophilic active agents, however, also present formulation problems, and although readily dissolved in the gastrointestinal environment, simple dissolution is not sufficient to provide efficient bioabsorption of the therapeutic agent. Barriers to absorption are presented by the mucous layer, the intestinal epithelial cell membrane, and the junctional structure such as tight junctions between the epithelial cells. Due to the presence of the negatively charged mucosal layer, significant electrostatic binding or repulsion of charged molecules can be encountered. The epithelial cell membranes are composed of phospholipid bilayers in which proteins are embedded via the hydrophobic segments. These bilayers at the apical and/or basolateral cell surface represent very strong barriers for transport of hydrophilic substances, including peptides and proteins. Frequently, hydrophilic therapeutic agents are also subject to enzymatic attack and are degraded before they can be presented to the absorption site.
Much effort has been expended to develop methods of overcoming these absorption barriers, in order to enhance the bioavailability of hydrophilic active agents. For example, the enzymatic barrier can be attacked by administering enzyme inhibitors to prevent or at least lessen the extent of presystemic degradation in the gastrointestinal tract (see, e.g., Bernkop-Schnurch (1998), “The use of inhibitory agents to overcome the enzymatic barrier to perorally administered therapeutic peptides and proteins,” Journal of Controlled Release 52:1-16). Other efforts have focused on, for example, the use of absorption promoters to enhance epithelial permeability (e.g., LeCluyse and Sutton (1997), “In vitro models for selection of development candidates. Permeability studies to define mechanisms of absorption enhancement,” Advanced Drug Delivery Reviews 23:163-183). However, the effectiveness of absorption enhancers such as permeability enhancers or enzyme inhibitors depends upon the ability of a pharmaceutical carrier to effectively present the absorption enhancers and the hydrophilic therapeutic agent to the absorption site, and prior efforts have not provided carriers which can do so efficiently. Moreover, maintaining effective carrier concentrations at the epithelium is not easily controlled in vivo. Too little carrier, or carrier concentrations only briefly maintained, may be ineffective. Too much carrier, or carrier concentrations maintained for too long, may result in compromised safety.
Traditional pharmaceutical suspensions of drugs are primarily composed of an aqueous continuous phase with little or no solubilized fraction. However, there are a few nonaqueous compositions on the market, e.g., Prometrium® (Solvay), an encapsulated formulation of micronized progesterone for oral administration, Accutane® (Roche), an encapsulated formulation of isotretinoin (cis-retinoic acid, indicated for treatment of severe nodular acne), also for oral administration, and Depo Provera® (Pharmacia), an injectable medroxyprogesterone acetate suspension. These nonaqueous dispersions have a very small fraction of drug in the dissolved state, typically far less than 10% of the total drug in the formulation. Moreover, because these traditional compositions lack any therapeutically significant solubilized fraction of drug, they are incapable of either enhancing the rate and extent of absorption or rapidly providing a therapeutically effective blood level of drug. For many types of drugs, these are significant limitations.
Current sustained release dosage forms provide a longer duration of action; however, their therapeutic utility is limited by the failure to provide any rapid onset, in turn a result of slow dissolution, low solubility, and the lack of any significant fraction of predissolved drug. For many therapeutic indications, such as pain, there is a need for both rapid onset of action and a longer duration of action.
With fundamental limitations presenting such enormous challenges for those attempting to formulate effective drug delivery systems, more complex formulation aspects have largely been ignored. For example, it would be highly desirable to provide a drug delivery system that not only provides for enhanced bioavailability and absorption of an active agent, but also exhibits long-term chemical and physical stability, and that, furthermore, may be readily tailored during manufacture to provide any of a number of unique drug release profiles, e.g., immediate release combined with delayed and/or sustained release, pulsatile release, targeted release, and the like.